Kleine-Levin Syndrome (KLS) is an orphan neuropsychiatric disorder, typically starting in childhood or adolescence. Its primary manifestation is a periodic hypersomnia (dramatic increases in sleep amounts) of central nervous system origin. These bouts of hypersomnia are also associated with cognitive disturbances and behavioral abnormalities such as hyperphagia, irritability and hypersexuality. Systematic research on the cause of this disease is inexistent, and is urgently needed due to the disabling nature of the disease and the lack of effective treatments. KLS has traditionally been considered an exceptionally rare disease, with fewer than 200 cases reported worldwide over the past 50 years. It now appears to be more common than previously expected. We have identified and characterized over 100 additional cases by active recruitment in the United States, Europe and Israel. The cause of this disease is unknown, but likely involves a major gene. KLS may be disproportionately frequent in the Jewish population, as the largest case series has been reported in this country, accounting for nearly one sixth of all patients reported worldwide. Our recent data from the United States also indicates increased ascertainment of KLS in Ashkenazi Jews, suggesting a genetic founder effect. Results of our recruitment further support the action of genetic factors, as we identified 5 familial cases among our 104 probands (4.8%), extending on case reports of multiplex families published in the literature over the last 40 years. Based on the above and due to the fact that it would be difficult to gather enough multiplex families to conduct traditional linkage studies, we propose to conduct a genome wide association study in 200 trios to identify a major KLS genetic susceptibility locus. A sub-analysis will be performed on 40 Jewish trios to take advantage of the potential founder effect. We will pursue regions of association through fine mapping and in silico analysis of gene content. Finally, we will identify and characterize candidate genes within the critical regions and identify variants in KLS patients. Identification of a Kleine-Levin Syndrome susceptibility locus will help to unravel the pathophysiology of this intriguing disease. This may also lead to novel insights in the control of sleep, appetite and other instinctual behaviors, with potential applications in other periodic neuropsychiatric disorders.